scholarly journals How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

2021 ◽  
Vol 10 (7) ◽  
pp. 1412
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Andrea Botticelli ◽  
Dario Trapani ◽  
Alessandro Parisi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Implementation ◽  
T Cell Therapy ◽  
Dismal Prognosis

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

Progress and prospects of immune checkpoint inhibitors in advanced gastric cancer

2021 ◽  
Author(s):  
Zhu Zeng ◽  
Biao Yang ◽  
Zhengyin Liao
Keyword(s):  
Gastric Cancer ◽  
Signaling Pathways ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Conventional Therapy ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Significant Survival ◽  
The Way

Gastric cancer, a digestive malignancy, is the sixth most frequent cancer and the second leading cause of tumor-related deaths worldwide. The emergence and advancement of immunotherapeutic agents has brought significant survival benefits for patients with gastric cancer and increasingly challenged the conventional therapy pattern involving chemotherapy and target drugs. Furthermore, these breakthroughs have paved the way for immunotherapy, especially with immune checkpoint inhibitors, which act by blocking specific signaling pathways, in particular the CTLA4 pathway and the PD-1/PD-L1 pathway. In this review we summarize the current trials of immune checkpoint inhibitors in GC and their predictive biomarkers, and discuss their present limitations.

scholarly journals New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

Programmed death (PD)-ligand 1 (L1) expression and mismatch repair (MMR) deficiency across tumor types: Candidates for checkpoint inhibitor based immunotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14622-e14622
Author(s):  
Seung Tae Kim ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
Young Suk Park ◽  
Ho Yeong Lim ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
The Status ◽  
Mmr Deficiency ◽  
Tumor Types

e14622 Background: The identification of biomarkers associated with response to therapeutic agents has changed the paradigm of cancer treatment into the precision medicine by identification of right targets across cancer types. PD-L1 expression and mutational or neoatigen burden (Mismatch repair (MMR) deficiency) have been actively studied as the predictive biomarkers for the response to immune checkpoint inhibitors. Methods: We have conducted the PD-L1 and hMLH1/MSH2 expression (MMR deficiency) as part of a clinical practice for 430 patients with advanced gastrointestinal (GI) cancer, genitourinary (GU) cancer or rare cancers between June 2012 and March 2016. Herein, we evaluated potential candidates who could be targeted to further immune checkpoint inhibitors. Results: In 430 patients, 414 (96.2%) patients were available to evaluate the status of PD-L1 expression by immunohistochemistry (IHC). Irrespective of tumor-types, overall 26.8% (111 of 414) exhibited expression of PD-L1 in tumor tissues. The PD-L1 expression was examined as follows; 33.5% in HCC, 31.0% in CRC, 27.3% in GC, 25.5% in melanoma, 18.8% in BTC, 16.7% in pancreatic cancer, 15.8% in sarcoma and 13.0% in GU cancer. Among the 394 patients available for MLH1/MSH2 expression, only 18 patients (4.5%) had the MMR-deficient tumors with complete loss of MLH1/MSH2 expression. The MMR-deficiency was observed as follows; 7.9% in GC, 6.7% in HCC, 4.0% in CRC, and 2.7% in sarcoma. On 382 patients evaluable for the status of both PD-L1 and MLH1/MSH2 expression, there was no the significant association between the PD-L1 expression and MLH1/MSH2 loss (p = 0.267) Conclusions: These data may provide useful information and background for future research for immune checkpoint inhibitor across tumor-types. As a single selection biomarker for immune checkpoint inhibitor in various tumor-types, neither the PD-L1 expression nor the MMR deficiency is optimal application in clinical trials.

scholarly journals Current status and future potential of predictive biomarkers for immune checkpoint inhibitors in gastric cancer

ESMO Open ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. e000791 ◽  
Author(s):  
Byung Woog Kang ◽  
Ian Chau
Keyword(s):  
Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gene Expression Signature ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Metastatic Gastric Cancer ◽  
Scientific Data ◽  
Current Status

Immunotherapy is revolutionising cancer treatment and has already emerged as standard treatment for patients with recurrent or metastatic gastric cancer (GC). Recent research has been focused on identifying robust predictive biomarkers for GC treated with immune checkpoint inhibitors (ICIs). The expression of programmed cell death protein-ligand-1 (PD-L1) is considered a manifestation of immune response evasion, and several studies have already reported the potential of PD-L1 expression as a predictive parameter for various human malignancies. Meanwhile, based on comprehensive molecular characterisation of GC, testing for Epstein-Barr virus and microsatellite instability is a potential predictive biomarker. Culminating evidence suggests that novel biomarkers, such as the tumour mutational burden and gene expression signature, could indicate the success of treatment with ICIs. However, the exact roles of these biomarkers in GC treated with ICIs remain unclear. Therefore, this study reviews recent scientific data on current and emerging biomarkers for ICIs in GC, which have potential to improve treatment outcomes.

Immune Checkpoint Inhibitor-Related Pneumonitis

Respiration ◽  
2020 ◽  
pp. 1-11
Author(s):  
Georgia Gomatou ◽  
Vasilios Tzilas ◽  
Elias Kotteas ◽  
Konstantinos Syrigos ◽  
Demosthenes Bouros
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Epidemiological Data ◽  
Future Research ◽  
Organ Specific ◽  
Cancer Types

Immune checkpoint inhibitors are novel agents that have been proved efficacious in a variety of cancer types, but they are associated with a unique set of organ-specific, immune-related adverse events. Among them, immune-related pneumonitis requires special attention because it is difficult to diagnose and potentially lethal. Accumulating real-world epidemiological data suggest that immune-related pneumonitis is more frequent than previously reported. Its diagnosis requires exclusion of other causes and assessment of radiographic features on high-resolution CT of the chest. Management of immune-related pneumonitis is based on the use of immunosuppressants. Future research should be focused on finding predictive biomarkers for immune-related pneumonitis as well as optimizing its management.

scholarly journals Current status of immunotherapy for advanced gastric cancer

2020 ◽  
Vol 51 (1) ◽  
pp. 20-27
Author(s):  
Akihito Kawazoe ◽  
Kohei Shitara ◽  
Narikazu Boku ◽  
Takaki Yoshikawa ◽  
Masanori Terashima
Keyword(s):  
Gastric Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Additional Treatment ◽  
Current Status ◽  
Number Of Patients

Abstract Recently, immune checkpoint inhibitors such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have improved the overall survival of various types of cancers including advanced gastric cancer (AGC). Until now, two ant-PD-1 inhibitors were approved for AGC in Japan: nivolumab as third- or later-line treatment for AGC and pembrolizumab for previously treated patients with microsatellite instability-high tumours. However, a limited number of patients achieved clinical benefit, highlighting the importance of the better selection of patients or additional treatment to overcome resistance to PD-1/PD-L1 blockade. This review focused on pivotal clinical trials, biomarkers and novel combination therapy of immune checkpoint inhibitors forAGC.

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